Engineering A "Hybrid Thymus" To Promote Transplant Tolerance
Sara AlFadil, MD1, Mi-Jeong Kim, PhD2, Marcos Iglesias Lozano, DVM, PhD1, Byoungchol Oh, DVM, PhD1, W.P. Andrew Lee, MD1, Gerald Brandacher, MD1, Thomas Serwold, PhD1, Giorgio Raimondi, PhD1.
1Johns Hopkins Medical Institute, Baltimore, MD, USA, 2Joslin Diabetes Center, Boston, MA, USA.
Purpose: Targeting the process of central (thymic) selection of developing T lymphocytes is the key tolerogenic mechanism of bone marrow transplantation (BM-Tx)-based protocols of transplant tolerance induction. However, they are not amenable to most transplant recipients. Thymic Epithelial Cells (TEC), a population of stromal cells residing in the thymus, exerts a major contribution to central selection. However, donor TEC do not develop following BM-Tx protocols. Therefore, we propose a new immunomodulatory strategy based on generating a donor-recipient "Hybrid Thymus", through donor TEC engraftment, to re-engineer the thymic microenvironment and achieve dominant central tolerance.
Methods: We developed our own protocol for isolating TEC via a combination of negative and positive selection. Purified BALB/c TEC were injected intrathymically into C57BL/6 with or without co-stimulation blockade (CTLA4-Ig). 14 and 28 days post-injection donor-TEC survival was assessed and peripheral T cells analyzed for changes in TCRbeta Vβ11 expression- a marker of negative selection.
Results: Our optimized purification protocol yields an average 70% TEC purity. As expected, unmanipulated animals promptly rejected TEC. However, CTLA4-Ig co-administration exerted a significant protection. In this latter group, the percentage of Vβ11+ T cells on d24 was significantly lower indicating functional activity of the engrafted donor TEC.
Conclusion: Our preliminary data show that the thymic engraftment, survival, and function of allogenic TEC can be promoted by CTLA4-Ig. These exciting results indicate that engineering a donor-recipient Hybrid Thymus is feasible and has the potential to promote a dominant regulation of alloreactivity that could be conducive to transplant tolerance induction.
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